Non-insulin-dependent diabetes mellitus (NIDDM) is a metabolic disease that affects about 5% to 7% of the population in western countries (and 10% of individuals over age 70). It is characterized by hyperglycemia and often accompanied by a number of other conditions, including hypertension, obesity and lipid disturbances. The underlying pathology is impaired beta-cell function of uncertain cause. Insulin resistance, which both precedes and predicts impaired glucose tolerance, may be the cause of beta-cell failure, or it may simply reveal the presence of a primary beta-cell defect.
Diet and exercise therapy alone are generally not successful in controlling hyperglycemia in NIDDM. In contrast to IDDM, in which insulin deficiency is the problem and insulin replacement the treatment, in NIDDM the pharmacological approach to hyperglycemia is more varied and more rapidly evolving. The data suggest that any improvement in the degree of blood glucose control will postpone development and slow the progression of microvascular complications. Treatment goals for people with diabetes that emphasize glycemic control are therefore recommended.
There are four classes of currently approved antidiabetic drugs in the United States, each of which have different effects on one or more of the pathogenetic abnormalities of NIDDM. The sulfonylurea agents all appear to act primarily by potentiating insulin secretion. In contrast, the biguanides have no direct effect on insulin secretion. Their mechanism or mechanisms of action are not completely understood but include a reduction in hepatic glucose production and perhaps an increase in peripheral insulin sensitivity and reduction in intestinal glucose absorption. A third class of drugs is the .alpha.-glucosidase inhibitors, which inhibit specific enzymes that break down starches in the small intestine, thereby delaying carbohydrate absorption and attenuating postprandial hyperglycemia. A fourth class of therapeutic drugs is the insulin preparations that supplement endogenous insulin.
Biguanides lower blood glucose primarily by reducing intestinal glucose absorption and hepatic glucose production. Metformin, (1,1-dimethylbiguanide) is rapidly absorbed and cleared through the kidneys. The drug has been shown to reduce fasting and postprandial blood glucose by an average of 2 to 3 mmol/L. It may also enhance insulin sensitivity at postreceptor levels and stimulate insulin-mediated glucose disposal, but it does not stimulate insulin secretion.
The number of patients who respond to biguanide therapy diminishes over the years because of a number of factors, e.g. drug noncompliance because of side effects, dietary noncompliance, weight gain, declining beta-cell function, and the increasing use of diabetogenic drugs such as glucocorticoids, thiazides, and beta-blockers. Metformin is contraindicated in patients with renal dysfunction or conditions that compromise renal function. The drug is also contraindicated in acute or chronic metabolic acidosis.
Compositions that are effective in treating non-insulin dependent diabetes, such as improved biguanide compositions, are of great interest. The invention described herein provides for such improved compositions and methods for their use.
Relevant Literature
Complexes formed between vanadium and biguanides have been described by Chakraborty and Das (1989) Analytica Chimica Acta 218:341-344; Syamal (1983) Ind. J. Pure & Applied Phys. 21:130-132; Calatayud et al. (1981) Afinidad XXXVIII:537-540; Babykutty et al. (1974) Thermochimica Acta 8:271-282. A complex of vanadium and 1,1-dimethylbiguanide is disclosed by Ray (1961) Chem. Rev. 61:313-359.
The insulin-like effect of the vanadate ion (VO.sub.4 .sup.3-) in vitro has been known since 1980, see Nature 284:556-558 (1980), when it was shown that the insulin-like stimulation of glucose oxidation in rat adipocytes was due to the vanadyl ion. In 1985, McNeill et al. (1985) Science 227: 1474-1477, reported that vanadate, when administered in drinking water, decreased the elevated blood glucose and prevented the depression of cardiac performance in rats made diabetic with streptozotocin (STZ). Subsequently, there has been interest in the insulin-mimetic effects of both vanadate and vanadyl, since Sakurai et al. (1980) Biochem. Biophys. Res. Comm. 96: 293-298, showed that vanadate is reduced in vivo to vanadyl.
Work by McNeill et al. (see Am. J. Physiol 257: H904-H911 (1989), Metabolism 38: 1022-1028 (1985), Diabetes 38: 1390-1395 (1989) and Can. J. Physiol & Pharmacol. 68: 486-491 (1990); U.S. Pat. Nos. 5,527,790; 5,300,496; has shown that vanadyl administered orally as vanadyl sulfate, or as vanadyl maltol complexes lowers blood glucose and blood lipids in STZ diabetic rats and prevents secondary complications of diabetes such as cataracts and cardiac dysfunction.